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Mismatch repair-dependent transcriptome changes in human cells treated with the methylating agent N-methyl-n'-nitro-N-nitrosoguanidine - Zurich Open Repository and Archive


di Pietro, M; Marra, G; Cejka, P; Stojic, L; Menigatti, M; Cattaruzza, M S; Jiricny, J (2003). Mismatch repair-dependent transcriptome changes in human cells treated with the methylating agent N-methyl-n'-nitro-N-nitrosoguanidine. Cancer Research, 63(23):8158-8166.

Abstract

DNA mismatch repair (MMR) plays a key role in the cytotoxic response of human cells to methylating agents, however, the cascade of events leading to cell cycle arrest and cell death has yet to be characterized. We studied the role of MMR in the transcriptional response to DNA methylation damage in two human cellular models: (a). the lymphoblastoid cell line TK6 and its derivative MT1, which is mutated in the MMR gene hMSH6; and (b). the epithelial cell line 293T Lalpha in which the expression of the MMR gene hMLH1 can be tightly regulated and p53 is inactivated. Upon N-methyl-N'-nitro-N-nitrosoguanidine treatment, only cells with functional MMR were killed, but the type of cytotoxic response differed. In TK6 cells, S-phase arrest and apoptosis were accompanied by a dramatic change in gene expression, notably, an up-regulation of several genes encoding growth inhibitors and proapoptotic factors both p53 dependent and independent. In contrast, the MMR-dependent transcriptional response in 293T Lalpha cells was substantially less pronounced than in TK6 cells, despite an efficient induction of a G(2)-M checkpoint and nonapoptotic cell death. Thus, we demonstrate that in human cells of different origin, MMR-mediated killing by methylating agents occurs through different pathways and regardless of the p53 status. Moreover, once DNA methylation damage has been processed by the MMR system, tumor cells might be committed to die, although one or more of their signaling pathways are impaired.

Abstract

DNA mismatch repair (MMR) plays a key role in the cytotoxic response of human cells to methylating agents, however, the cascade of events leading to cell cycle arrest and cell death has yet to be characterized. We studied the role of MMR in the transcriptional response to DNA methylation damage in two human cellular models: (a). the lymphoblastoid cell line TK6 and its derivative MT1, which is mutated in the MMR gene hMSH6; and (b). the epithelial cell line 293T Lalpha in which the expression of the MMR gene hMLH1 can be tightly regulated and p53 is inactivated. Upon N-methyl-N'-nitro-N-nitrosoguanidine treatment, only cells with functional MMR were killed, but the type of cytotoxic response differed. In TK6 cells, S-phase arrest and apoptosis were accompanied by a dramatic change in gene expression, notably, an up-regulation of several genes encoding growth inhibitors and proapoptotic factors both p53 dependent and independent. In contrast, the MMR-dependent transcriptional response in 293T Lalpha cells was substantially less pronounced than in TK6 cells, despite an efficient induction of a G(2)-M checkpoint and nonapoptotic cell death. Thus, we demonstrate that in human cells of different origin, MMR-mediated killing by methylating agents occurs through different pathways and regardless of the p53 status. Moreover, once DNA methylation damage has been processed by the MMR system, tumor cells might be committed to die, although one or more of their signaling pathways are impaired.

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15 citations in Web of Science®
18 citations in Scopus®
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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Molecular Cancer Research
07 Faculty of Science > Institute of Molecular Cancer Research
Dewey Decimal Classification:570 Life sciences; biology
Language:English
Date:2003
Deposited On:09 Jul 2010 07:10
Last Modified:05 Apr 2016 13:57
Publisher:American Association for Cancer Research
ISSN:0008-5472
PubMed ID:14678970

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